Electrotransport agent delivery method and apparatus

ABSTRACT

A method of increasing the delivery efficiency of an agent through a body surface by electrotransport is disclosed wherein the electrotransport current is applied for durations at a higher current density values followed by durations of lower current density values wherein the higher current density applications transform the body surface to an enhanced, non-transitory agent delivery efficiency state.

TECHNICAL FIELD

The present invention generally concerns enhanced stability, generallymore controlled, methods for the electrically assisted delivery of atherapeutic agent in vivo. This invention also concerns apparatuses ordevices for increased efficiency or increased stabilityelectrotransport. This invention is particularly applicable to theelectrotransport of highly potent therapeutic agents which are to bedelivered at small dosage levels.

BACKGROUND OF THE INVENTION

The present invention concerns in vivo methods and apparatuses fortransdermal electrotransport delivery of therapeutic agents, typicallydrugs. Herein the terms “electrotransport”, “iontophoresis” and“iontophoretic” are used to refer to methods and apparatus fortransdermal delivery of therapeutic agents, whether charged oruncharged, by means of an applied electromotive force to anagent-containing reservoir. The particular therapeutic agent to bedelivered may be completely charged (i.e., 100% ionized), completelyuncharged, or partly charged and partly neutral. The therapeutic agentor species may be delivered by electromigration, electroosmosis or acombination of these processes. Electroosmosis has also been referred toas electrohydrokinesis, electro-convection, and electrically-inducedosmosis. In general, electroosmosis of a therapeutic species into atissue results from the migration of solvent, in which the species iscontained, as a result of the application of electromotive force to areservoir containing the therapeutic species.

As used herein, the terms “electrotransport”, “iontophoresis” and“iontophoretic” refer to (1) the delivery of charged drugs or agents byelectromigration, (2) the delivery of uncharged drugs or agents by theprocess of electroosmosis, (3) the delivery of species by transportprocesses which include an electroporation step (See, e.g., Weaver etal. U.S. Pat. No. 5,019,034), (4) the delivery of charged drugs oragents by the combined processes of electromigration and electroosmosis,and/or (5) the delivery of a mixture of charged and uncharged drugs oragents by the combined processes of electromigration and electroosmosis,combinations of the above processes to deliver either or both of chargedor uncharged species.

Iontophoretic devices for delivering ionized drugs through the skin havebeen known since the early 1900's. Deutsch U.S. Pat. No. 410,009 (1934)describes an iontophoretic device which overcame one of thedisadvantages of such early devices, namely, that the patient needed tobe immobilized near a source of electric current. The Deutsch device waspowered by a galvanic cell formed from the electrodes and the materialcontaining the drug to be transdermally delivered. The galvanic cellproduced the current necessary for iontophoretically delivering thedrug. This device allowed the patient to move around duringiontophoretic drug delivery and thus imposed substantially lessinterference with the patient's daily activities.

In presently known electrotransport devices, at least two electrodes orelectrode assemblies are used. Both electrodes/electrode assemblies aredisposed so as to be in intimate electrical contact with some portion ofthe skin of the body. One electrode, called the active or donorelectrode, is the electrode from which the ionic substance, agent,medicament, drug precursor or drug is delivered into the body throughthe skin by iontophoresis. The other electrode, called the counter orreturn electrode, serves to close the electrical circuit through thebody. In conjunction with the patient's skin contacted by theelectrodes, the circuit is completed by connection of the electrodes toa source of electrical energy, e.g., a battery. For example, if theionic substance to be delivered into the body is positively charged,then the positive electrode (the anode) will be the active electrode andthe negative electrode (the cathode) will serve to complete the circuit.If the ionic substance to be delivered is negatively charged, then thecathodic electrode will be the active electrode and the anodic electrodewill be the counter electrode.

As is discussed above, electrotransport delivery devices can be used todeliver uncharged drugs or agents into the body, e.g, transdermally.This is accomplished by a process called electroosmosis. Electroosmosisis the (e.g., transdermal) flux of a liquid solvent (e.g., the liquidsolvent containing the uncharged drug or agent) which is induced by thepresence of an electric field imposed across the skin by the donorelectrode.

Electrotransport electrode assemblies/devices generally include areservoir or source of the beneficial agent or drug (preferably anionized or ionizable species or a precursor of such species), which isto be delivered into the body by electrotransport. Examples of suchreservoirs or sources include a pouch as described in Jacobsen U.S. Pat.No. 4,250,878, a pre-formed gel body as disclosed in Webster U.S. Pat.No. 4,382,529 and Ariura, et al. U.S. Pat. No. 4,474,570 and areceptacle containing a liquid solution as disclosed in Sanderson, etal. U.S. Pat. No. 4,722,726. Such drug reservoirs are connected to theanode or the cathode of an electrotransport device to provide a fixed orrenewable source of one or more desired species or agents. Electricalcurrent is typically applied to the reservoir by means of a currentdistributing member, which may take the form of a metal plate, a foillayer, a conductive screen, or a polymer film loaded with anelectrically conductive filler such as silver or carbon particles. Thecurrent distributing member, including any appropriate connectors andassociated connective conductors such as leads, and the reservoircomprise an electrode assembly herein.

The prior art has recognized that “competitive” ionic species having thesame charge (i.e., the same sign) as the drug ions being delivered byelectrotransport have a negative impact on electrotransport drugdelivery efficiency. The efficiency (E) of electrotransport delivery ofa particular species is defined herein as the rate of electrotransportdelivery of that species per unit of applied electrotransport current(mg/mA-h). The prior art further recognized that competitive ionicspecies were inherently produced during operation of these devices. Thecompetitive species produced are dependent upon the type of electrodematerial which is in contact with the drug solution. For example, if theelectrode is composed of an electrochemically inert material (e.g.,platinum or stainless steel), the electrochemical charge transferreaction occurring at the electrode surface tended to be waterelectrolysis since water is the overwhelmingly preferred liquid solventused in electrotransport drug solutions. Water electroysis producescompeting hydronium ions at the anode (in the case of cationicelectrotransport drug delivery) and competing hydroxyl ions at thecathode (in the case of anionic electrotransport drug delivery). On theother hand, if the electrode is composed of an electrochemicallyoxidizable or reducible species, then the electrode itself is oxidizedor reduced to form a competitive ionic species. For example, Unterekeret al U.S. Pat. No. 5,135,477 and Petelenz et al U.S. Pat. No. 4,752,285recognize that competitive ionic species are electrochemically generatedat both the anode and cathode of an electrotransport delivery device. Inthe case of an electrotransport delivery device having a silver anodicdonor electrode, application of current through the silver anode causesthe silver to become oxidized (Ag→Ag⁺+e⁻) thereby forming silver cationswhich compete with the cationic drug for delivery into the skin byelectrotransport. The Untereker and Petelenz patents teach thatproviding a cationic drug in the form of a halide salt causes a chemicalreaction which removes the “competing” silver ions from the donorsolution (i.e., by reacting the silver ions with the halide counter ionof the drug to form a water insoluble silver halide precipitate;Ag⁺+X⁻→AgX), thereby achieving higher drug delivery efficiency. Inaddition to these patents, Phipps et al PCT/US95/04497 filed on Apr. 7,1995 teaches the use of supplementary chloride ion sources in the formof high molecular weight chloride resins in the donor reservoir of atransdermal electrotransport delivery device. These resins are highlyeffective at providing sufficient chloride for preventing silver ionmigration, yet because of the high molecular weight of the resin cation,the resin cation is effectively immobile and hence cannot compete withthe drug cation for delivery into the body.

The prior art has long recognized that the application of electriccurrent through skin causes the electrical resistance of the skin todecrease. See, for example, Haak et al U.S. Pat. No. 5,374,242 (FIG. 3).Thus, as the electrical resistance of the skin drops, lower voltages areneeded to drive a particular level of electrotransport current throughthe skin. This same phenomenon is observed in a technique referred to as“electroporation” of the skin. See Weaver et al U.S. Pat. No. 5,019,034.Electroporation involves the application of short, high voltageelectrical pulses to produce what is characterized as a transient (e.g.,decreasing to normal levels in 10 to 120 sec. for excised frog skin)increase in tissue permeability. Electroporation is also characterizedby the creation of pores in lipid membranes due to reversible electricalbreakdown. Electroporation does not, itself, deliver any drug but merelyprepares the tissue thereby treated for delivery of drug by any of anumber of techniques, one of which is iontophoresis.

DISCLOSURE OF THE INVENTION

The present invention arises from the discovery that, under specifiedconditions of applied electrotransport current density (generallyexpressed in units of microamperes/cm² herein) and application time theelectrotransport transdermal drug delivery efficiency E, in units ofmg/mAh defined as the rate of transdermal electrotransport drug delivery(mg/h) per unit of applied electrotransport current (mA), is enhanced.The enhancement of the skin's electrotransport efficiency has been foundto be non-transitory, i.e., to last for at least several minutes toseveral hours or longer after application of this invention. Thisinvention induces (e.g., through a pre-treatment or pre-application stepin which species are delivered) a high efficiency drug-transmissivestate in the skin to which it is applied. The induced, high efficiencystate continues and can be utilized to deliver drug or other therapeuticagent transdermally with increased efficiency. In usual circumstances,this will permit delivery of drug with more precise control and at alower current. This invention has only been found in the transdermaldeliver of drug or agent through intact living skin or tissue, i.e., invivo.

Generally speaking, the pretreatment step of this invention involves aninitial delivery of a charged species, at a pre-determined or thresholdcurrent density for a predetermined period of time (e.g., for apredetermined pulse width) through the site of drug delivery, e.g.,intact skin. In this manner, the pre-treated skin exhibits astatistically significant, non-transitory increase in drug deliveryefficiency relative to skin which has not been so treated. Generallyspeaking, utilization of this invention will significantly increase thedrug/agent delivery efficiency or reduce or eliminate efficiencyvariability of the skin segment or patch which is so treated. (Drugdelivery efficiency, in some aspects of its meaning is analogous totransport number. Transport number is a unitless quantity, less thanone, indicating the fractional charge carried by a particular ionicspecies, e.g., a drug or agent, during electrotransport. Efficiency, asdefined herein, is more broadly applicable to include the transport ofuncharged species and is thought to be more reflective of the scope ofthe invention.) Since efficiency remains elevated or less variable afterutilization of this invention (relative to untreated skin), utilizationof this invention permits the delivery of drug or agent through intactskin by electrotransport with increased control and efficiency.

Briefly, in one aspect, the present invention is a method ofelectrotransport drug or agent delivery through a body surface involvingthe steps of:

-   -   delivering ionic species by electrotransport at a sufficient        current density and over a sufficient period which will change        or convert the transport efficiency of the body surface through        which the ionic species is delivered to a non-transitory state        of higher species delivery efficiency; and thereafter    -   delivering drug or agent through the body surface while in its        high efficiency state.

In a preferred practice, current density and species delivery time areselected to maintain the higher efficiency species delivery state of thebody surface. This invention also includes the preferred practice ofintentionally renewing the highly efficient species delivery state so asto optimize drug delivery efficiency if drug or agent deliveryconditions are used which do not periodically renew it. In anotherpreferred practice, the present invention is utilized to deliver drug oragent transdermally, i.e., through intact skin. In yet a furtherpreferred practice, the present invention is used to deliver drug oragent through intact, live, human skin.

In the practice of this invention, the precise current density andtreatment time period needed to convert untreated skin to a highlytransmissive state have been found to be fairly specific to the drug ortherapeutic agent to be delivered. However, for the electrotransportdelivery of analgesics, which have been the primary focus of thisinvention, a treatment of the body site through which drug is to bedelivered for a time period of at least 10 msec to 20 minutes or longer,e.g., 30 minutes, at a current density of about 40 μA/cm², preferably atleast about 50 μA/cm² and most preferably about 70 μA/cm² appears toconvert the body site so treated to a highly drug transmissive state asdefined in this invention. In essence, were one to plot efficiency (E)versus current density, this invention arises because of the surprisingand unexpected discovery that efficiency is highly dependent (i.e., itchanges) at current densities in the range of about 0 to about 30μA/cm², is moderately dependent upon current density in the range of 40to about 70 uA/cm² and is relatively flat at current densities in excessof about 70 μA/cm². This surprising and unexpected change in efficiency(in theory, efficiency is not predicted to change with increasingcurrent density) permits delivery of drug in the higher efficiency statewith significantly enhanced efficiency.

A second surprising and unexpected result is achieved in the practice ofthe present invention, i.e., the change to the more transmissive stateexhibits hysteresis. In other words, when the skin site has beenconverted to a highly efficient agent transmissive state by delivery ofagent at the requisite current density and for the specified timeperiod, reduction in current (and therefore current density) does notcause the skin to return to its initial, lower efficiency state. Thisobservation respecting in vivo drug delivery can be critically importantto electrotransport system design.

“Non-transitory” herein, when referring to the high efficiency drugdelivery state, means of sufficient length to permit drug to bedelivered to achieve a therapeutic effect. Thus, for example, arelatively inexpensive ionic species may be used to trigger conversionof, e.g., a skin site, to a highly efficient and more stable ionicspecies delivery state, and thereafter relatively more expensive drug oragent may be delivered at greater efficiency and stability byelectrotransport. Where the drug or agent is inexpensive, it may be usedto convert the body delivery site to the highly efficient and morestable state, and thereafter may be delivered with greater efficiency,i.e., at lower current density and at greater stability.

The term “higher efficiency state” as used herein means conversion ofany particular body or skin site to a state in which drug or agentdelivery is at least 10% (preferably 20%) more efficient than the sameskin site prior to conversion in accordance with this invention.Generally, the parameter which will be most reflective of thisefficiency increase will be the efficiency. The term “greater stabilitystate” as used herein means conversion from a state of more variabledrug delivery to one of less variability by exposure of the body site toa current density above the critical current density for a time periodlonger than the critical time, t_(c). Critical current density forpurposes of increased stability, has been found to be as low as about 40μA/cm².

In a preferred practice of this invention, it is desirable to be able tochange, precisely, drug dosage after the body site has been converted toa highly efficient drug or agent delivery state. In accordance with thisinvention, total drug or agent delivered (i.e., dosage) may be adjustedwhile maintaining the required current density to retain the mostefficient and stable state, i.e., independent of average current appliedby the alternatives of: (a) in a pulsed output electrotransport system,adjustment of device duty cycle while maintaining average currentdensity above the critical current density; (b) in an electrotransportdevice employing a pulsed output, maintaining constant peak current andpulse width while adjusting pulse frequency to adjust total drug oragent delivered, or (c) the intentional inclusion in and delivery froman “in line” (i.e., to deliver drug) component or subassembly of anelectrotransport device of competitive co-ions not having a therapeuticeffect converts the system to a stable drug flux at current densityabove the critical current density. Delivery of competitive co-ions, fora given current, in addition to the drug or agent ions, providesadequate current density but permits controlled modification of thequantity of therapeutic agent delivered. Delivery of competitive co-ionsfrom, e.g., the drug reservoir, also reduces potentially expensive andpotent total drug or agent delivered. Another way to use an inexpensiveionic species to trigger the skin conversion is to utilize a reversepolarity system. One example of such a system would first drive theanionic drug counter ion from the donor reservoir and the cationicsubstance from the counter reservoir for the time required to convertthe skin to a high efficiency state and then reverses polarity, therebymoving the drug cation into the skin.

In one practice of this invention, the highly potent analgesic drug,fentanyl, is delivered at very low current density under conditionswhich fentanyl delivery tends to be unstable, i.e., to exhibitunacceptable drug delivery variability. Addition of a chloride salt,e.g., sodium chloride, to the electrode assembly drug reservoir providessufficient co-deliverable, competitive ion (i.e. Na⁺) to stabilizefentanyl delivery. In this manner, fentanyl efficiency variability alsois reduced or eliminated. These and other aspects of this invention willbe discussed below.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the present invention, as well as otherobjects and advantages thereof, will become apparent upon considerationof the following modes for carrying out the invention especially whentaken with the accompanying drawings, wherein:

FIG. 1 is a graph of transdermal electrotransport drug deliveryefficiency (E) versus applied electrotransport current density (l_(d))for in vivo delivery of fentanyl;

FIG. 2 is a graph of electrotransport current versus time, showing threepulsed current waveforms having differing duty cycles;

FIG. 3 is an exploded perspective view of a transdermal electrotransportdrug delivery device which can be used in accordance with the method ofthe present invention.

FIG. 4 is a depiction of two waveforms having the same peak current andpulse width but different pulse rates.

FIG. 5 is a graph of mean serum fentanyl concentrations showing howinitial bolus doses increase fentanyl delivery through a 24 hour period;

FIG. 6 is average serum fentanyl concentration, as a function of time,for several current densities;

FIG. 7 is a graph of serum fentanyl concentrations vs. time for deliveryof fentanyl at 3 different frequencies.

FIG. 8 is a graph of delivery profile for goserelin.

MODES FOR CARRYING OUT THE INVENTION

The present invention is based upon the discovery that the efficiency(E) of transdermal electrotransport drug delivery is, at least at lowerapplied electrotransport current densities, dependent on the appliedelectrotransport current density (l_(d)). This phenomenon is illustratedgraphically in FIG. 1. Specifically, we have discovered that whenelectrotransport current densities above a critical current densitylevel, l_(c), are applied to the skin of living animals for sufficientperiods of time longer than a critical period of time, t_(c), on theorder of several minutes, the drug delivery efficiency (E) increases toa plateau level and is no longer dependent upon the level of appliedcurrent density. It is important to note that the effect we arereporting has nothing to do with the widely held belief that transdermalelectrotransport drug flux is dependent (i.e., linearly dependent) uponthe level of applied electrotransport current. Our discovery is thatthis widely held belief is only true at current densities above acritical current density level l_(c). Thus, we have discovered that, atapplied current densities below the critical current density levell_(c), the rate of electrotransport drug delivery per unit of appliedelectrotransport current is not constant as have been previouslyassumed. Not only is the electrotransport drug delivery efficiency (E)variable at lower current densities, it is also lower than at currentdensities above the critical level l_(c). Thus, at applied currentdensities below l_(c), the electrotransport delivery is less efficientin that more electrotransport current must be applied to deliver apredetermined amount of drug. A still further aspect of our discovery isthat the interpatient variability in transdermal electrotransportefficiency is lower at applied current densities above the criticallevel l_(c) and higher at applied current density levels below thecritical level l_(c).

In general, the critical current density level l_(c) for human skin isin the range of about 40 to 100 uA/cm², although the critical levell_(c) will vary somewhat with the particular drug being deliveredbetween individuals, and between different skin locations in the sameindividual. Typically, a current density at or above the critical levell_(c) need only be applied for several milliseconds to several minutes(e.g., 2 to 8 minutes) before the skin enters the high efficiency drugtransfer state. However, applied current densities below the criticallevel l_(c) are unable to transform the skin into the high efficiencytransfer state, even when these low level current densities are appliedfor extended periods of time (e.g., up to several hours application).This transformation of the skin to a higher efficiency delivery stateoccurs only in living animals and does not occur with excised skin takenfrom living or dead animals, i.e., the skin transformation has not beenfound to occur when in vitro flux studies were run.

Once the skin has been transformed into the high efficiency transferstate, it tends to remain in that state for an extended period of time(e.g., up to 24 hours) even if no further electrotransport current isthereafter applied to the skin or if only low level current densities(i.e., current densities less than the critical level l_(c)) arethereafter applied to the skin. (This result is illustrated in FIG. 5and is discussed below.) The “transformed” skin is in general only thoseskin sites which are in contact with the donor and counterelectrodes/reservoirs of the electrotransport delivery device andthrough which skin sites the applied current has been passed. Thus, if askin site on the arm of a patient has been transformed by application ofelectrotransport current densities above the critical level l_(c), theskin on the legs, torso or other arm of the patient does not becometransformed. The skin transformation of this invention is a localizedphenomenon which is limited to those portions of the skin to which thedonor and counter electrodes/reservoirs are attached. Since the skin atthe counter electrode site also is converted, alternating polarityapplications are within the scope of this invention.

Our discovery is particularly critical in those transdermalelectrotransport drug delivery regimens wherein the drug is delivered attwo (or more) different dosing levels, one dosing level beingadministered at a current density below the critical level l_(c) andanother dosing level being administered at a current density above thecritical level. For example, many drugs are adapted to be administeredat a low dose baseline rate for extended periods, the baseline ratebeing interrupted periodically by periods of higher dosing. Examples ofdrugs which are administered in this fashion include (1) analgesics,such as fentanyl and sufentanil, which are administered at a lowbaseline level to treat (e.g., chronic) pain and which are periodicallydelivered at higher doses to treat more severe episodes of pain; (2)anti-emetics, such as the 5HT3 receptor antagonists ondansetron andgranisetron, which are administered continuously at low levels (e.g.,during weeks over which a patient is undergoing chemotherapy) and whichare periodically administered at higher dosing levels (i.e., during theactual chemotherapeutic administration); (3) anti-epileptics, such asphenytoin, which are delivered continuously at low baseline levels andperiodically at higher levels when the patient is undergoing anepileptic seizure; and (4) anti-diabetic drugs, such as insulins, whichcan be delivered continuously at low baseline levels and periodically(e.g., during or after meals) at higher levels. The problem encounteredwith this type of transdermal electrotransport drug administration isthat once the drug is administered at the higher dosing rate (with theapplied current density above the critical level, l_(c)), when theapplied electrotransport current is readjusted to apply the originallower baseline level, the transdermal electrotransport drug flux doesnot return to the same baseline level. The drug flux instead falls to alevel somewhere between the original baseline rate and the high dosingrate, because the skin has been transformed into a higher efficiencydrug delivery state. For example, if the efficiency is enhanced by afactor of two, after the skin has experienced a current density abovethe critical current density, and then the current is lowered to theoriginal base line current, the drug delivery rate would be twice thatexperienced before the transformation. The higher baseline rate couldresult in a drug overdose if the electrotransport system does notcompensate for this shift in efficiency. To eliminate this problem, theelectrotransport system should reduce the current applied (e.g., by afactor of two) after the skin has experienced a current density greaterthan l_(c). With reference to FIG. 1, data point 2 is a likelyefficiency that would be experienced at the drug delivery site werecurrent (and therefor current density) reduced after exposure of thebody site to current density l_(c). At data point “2” efficiency isbetween that of l_(c) and an l_(d) (at 20 μA/cm²) before skin exposureto l_(c) was made.

A more elegant approach to this problem is to apply a pulsedelectrotransport current to the skin, the pulsing current having amagnitude above the critical level l_(c), and to modify the duty cycleof the pulses to increase or decrease the amount of drug delivered. Dutycycle is the ratio of “on” time interval to the period of time of onecycle (i.e., the ratio of the pulse-duration time to the pulse-period)and is usually expressed as a percent. For example, if a device is “on”for 500 ms of a 1 sec cycle, then the device is operating in a 50% dutycycle. In this practice of the invention, the magnitude of the currentpulses is selected in view of the known area of the surface from whichdrug is delivered, thereby defining a fixed and known current density(i.e., the ratio of current to the area from which current flows). Thus,if it is decided, based upon application of the above principles, that aspecific maximum current for a given anode surface area e.g., l_(max),will provide the enhanced efficiency drug delivery discussed above, thenby increasing or decreasing the duty cycle, the amount of drug deliveredat the high efficiency state can be increased or decreased withoutcausing the maximum applied current density to change. In choosing theparameters of drug delivery if using this approach, the amplitude of thecurrent pulses is selected so that the resulting current densitytransforms the skin into the high efficiency state and the duty cycle ofthe current pulses is altered to adjust the drug delivery rate (i.e., alow dose of drug is administered by a high density (i.e., greater thanl_(c)) pulsing current having a low duty cycle and a high dose of drugis administered by the same magnitude current density but being pulsedat a pulse width corresponding to a high duty cycle.

This aspect of the invention is more specifically illustrated in FIG. 2where waveforms for three different pulsing electrotransport currents ofthe same frequency are shown. In FIG. 2 time is illustrated on thehorizontal axis, while current amplitude is illustrated on the verticalaxis. The three current waveforms shown in FIG. 2 all have the samemagnitude, and hence the same current density l_(max) for anelectrotransport delivery device of any one size. This particularcurrent density l_(max) is greater than the critical current densitylevel l_(c). The three current waveforms have differing duty cycles,which is the percentage of time during which the current is applied. Thethree waveforms have duty cycles of 75% (top waveform), 50% (middlewaveform) and 25% (bottom waveform). Thus, the 25% duty cycle waveformdelivers drug transdermally by electrotransport at about one-half thedosing level of the 50% duty cycle waveform and about one-third thedosing level of the 75% duty cycle waveform. All three waveformsadminister drug transdermally by electrotransport through skin which istransformed into the high efficiency transfer state by reason of l_(max)being greater than l_(c).

In a further practice of this invention, the pulsing frequency of apulsed current waveform is adjusted to control the overall quantity ofdrug delivered while holding the pulse width constant and maintainingthe amplitude of current pulses above l_(c). In this manner, currentdensity is maintained at or above the level which transforms the skininto the high efficiency state. Exemplary of this, a device employing apulsed current waveform having pulses with a magnitude of 0.2 mA, apulse width of 10 m sec, and a frequency of 10 Hz will deliver roughlyhalf as much drug as the same device run at a frequency of 20 Hz. Givena constant drug delivery area, e.g., of an electrode assembly, theapplied current densities of these two devices is the same and is abovethe high efficiency critical level l_(c) so that both devices deliverdrug transdermally by electrotransport with higher efficiency and lowervariability compared to devices which apply electrotransport current atcurrent densities below the critical level l_(c). From these twoexamples of the invention one skilled in this art will appreciate that acombination of frequency and duty cycle may be used to alter the rate ofdrug delivery while maintaining l_(max) above l_(c). FIG. 4 shows thewaveforms for a device operated to have a constant 9 msec pulse width,the frequency for a device operated according to the lower waveformbeing ½ that of a device operated according to the upper waveform (i.e.,50 Hz versus 100 Hz).

As is noted above, agent delivery efficiency is increased by exposure ofthe site to current density above l_(c) and for a time period greaterthan a critical time, t_(c). Generally speaking, for a pulsingelectrotransport device, pulse width must exceed t_(c). Thus, t_(c), ina practice of this invention using pulsed current electrotransportdevices and for delivery of fentanyl, falls between about 0.5 msec and30 msec. It is believed that the minimum pulse width to causetransformation to the higher efficiency state is greater than about 10msec for fentanyl.

Table 1 shows data which support the above observation. Table 1 showsdrug delivery efficiency data for a device programmed to run atfrequencies of 1 Hz, 10 Hz and 625 Hz. A 31% duty cycle was employed.

TABLE 1 Rate of Fentanyl Delivery μg/hr. Without After Pulse Width BolusTreatment Bolus Treatment* 625 0.5 msec 7  34  10 31 msec 52** 52** 1320 msec 48** 48** *“Bolus Treatment” means a direct current bolusdelivery of fentanyl for a period of 30 minutes at a current density of0.1 mA/cm². **The numbers in these two columns are the same because evenat a pulse width as short as 31 msec, the skin site had alreadytransformed to its highly efficient state.

Table 1 also indicates the existence of what is called capacitive lossas pulsing frequency is increased at a given duty cycle. Capacitive losssimply means a portion of the leading edge of each pulse is consumed bythe process of charging the skin without delivering drug. The higher thefrequency, the greater (relatively speaking) the capacitive loss foreach pulse.

Table 1 also shows that until a critical pulse width is achieved,regardless of frequency, no transformation of the body site agentdelivery efficiency occurs.

Pulsed current electrotransport devices are well known in the art. Suchdevices are described in numerous technical articles and the patentliterature including Bagniefski et al. “A Comparison of Pulsed andContinuous Current Iontophoresis”, Journal of Controlled Release.113-122, (1090); McNichols et al., U.S. Pat. No. 5,047,007; Sibalis U.S.Pat. No. 5,135,478; R. Burnette et al. “Influence of Constant CurrentIontophoresis on the Impedance and Passive Na⁺ Permeability of ExcisedNude Mouse Skin”, 77 J. Pharmaceutical Sciences 492 (1988); Pikal et al,“Study of the Mechanisms of Flux Enhancement Through Hairless Mouse Skinby Pulsed DC Iontophoresis,” 8 Pharmaceutical Research 365 (1991).

Another method of transdermally delivering a therapeutic agent (e.g., adrug) by electrotransport at an applied current density at or above thecritical level l_(c) but at a lower dosing/delivery rate (i.e., a ratewhich requires a current lower than that achieved when applying currentl_(c)) involves the intentional introduction of competitive ions havingthe same (i.e., same polarity) charge as the therapeutic agent ions.This approach, under the specific conditions described, permits drugdosage control as well as providing enhanced stability and enhancedefficiency of electrotransport of therapeutic agent. This approach isgenerally discouraged in the patent literature because it otherwisetends to reduce drug delivery efficiency. This aspect of this inventionis particularly applicable to electrotransport delivery of drugs oragents which have very low therapeutic levels or therapeuticconcentrations. Generally speaking, this aspect of the present inventionis particularly applicable to the electrotransport delivery of highlypotent drugs or other therapeutic agents.

The competitive ionic species can be loaded into the donor reservoir(e.g., a biocompatible salt is added to the donor reservoir) beforeelectrotransport agent delivery and/or can be generated in situ duringthe operation of the electrotransport device. The amount of thecompetitive species intentionally added will be specific to the drug oragents to be delivered and the relative electrophoretic mobilities ofthe drug ions and the competing ionic species. Generally, thecompetitive species will be ionic and should have deliverycharacteristics similar to those of the drug being delivered. Thequantity of co-delivered species to be added is selected so that thetotal current density is raised above the critical current density,l_(c), where the ionic species efficiency is normalized or stabilized sothat variation of efficiency is no longer experienced.

U.S. Pat. No. 5,080,646 (“Membrane for Electrotransport Transdermal DrugDelivery”) to Theeuwes et al. contains a detailed discussion of theprocesses involved in the transport of species through a biologicalsurface such as skin, mucosa, or tissue. The Theeuwes et al '646provides a mathematical analysis which permits one skilled in this art,when unacceptable random variability of electrically-assisted drug fluxis experienced, to select a suitable quantity and species of competitiveco-ion to be delivered along with the drug or agent. The teaching of theTheeuwes et al '646 patent is incorporated by reference herein.

In a second aspect of the present invention, the transdermalelectrotransport drug flux may be increased, when using a pulsingelectrotransport driving current, by maintaining the pulsing frequencybetween less than about 100 Hz, and preferably less than about 10 Hz.The term “pulsing electrotransport driving current” as used herein meansa current which in essence, provides sufficient pulse width to effecttransformation of the skin to the higher efficiency drug delivery state.This then provides the second of the two necessary and sufficientparameters (after current density l_(c)) which must be satisfied toapply this invention. As was noted above, pulsing frequencies in therelatively low ranges discussed here combined with sufficient dutycycle, provide the pulse width needed for in vivo skin drug deliveryefficiency to increase. For example, a frequency of about 10 Hz (i.e., aperiod of about 100 msec) and a duty cycle of 31% was found to provide apulse width long enough to induce a skin efficiency increase to deliverfentanyl at a current density of 0.1 mA/cm².

Reference is now made to FIG. 3 which depicts an exemplaryelectrotransport device which can be used in accordance with the presentinvention. FIG. 3 shows a perspective exploded view of anelectrotransport device 10 having an activation switch in the form of apush button switch 12 and a display in the form of a light emittingdiode (LED) 14. Device 10 comprises an upper housing 16, a circuit boardassembly 18, a lower housing 20, anode electrode 22, cathode electrode24, anode reservoir 26, cathode reservoir 28 and skin-compatibleadhesive 30. Upper housing 16 has lateral wings 15 which assist inholding device 10 on a patient's skin. Upper housing 16 is preferablycomposed of an injection moldable elastomer (e.g., ethylene vinylacetate). Printed circuit board assembly 18 comprises an integratedcircuit 19 coupled to discrete electrical components 40 and battery 32.Circuit board assembly 18 is attached to housing 16 by posts (not shownin FIG. 3) passing through openings 13 a and 13 b, the ends of the postsbeing heated/melted in order to heat stake the circuit board assembly 18to the housing 16. Lower housing 20 is attached to the upper housing 16by means of adhesive 30, the upper surface 34 of adhesive 30 beingadhered to both lower housing 20 and upper housing 16 including thebottom surfaces of wings 15.

Shown (partially) on the underside of circuit board assembly 18 is abattery 32, which is preferably a button cell battery and mostpreferably a lithium cell. Other types of batteries may also be employedto power device 10.

The circuit outputs (not shown in FIG. 3) of the circuit board assembly18 make electrical contact with the electrodes 24 and 22 throughopenings 23,23′ in the depressions 25,25′ formed in lower housing, bymeans of electrically conductive adhesive strips 42,42′. Electrodes 22and 24, in turn, are in direct mechanical and electrical contact withthe top sides 44′,44 of drug reservoirs 26 and 28. The bottom sides46′,46 of drug reservoirs 26,28 contact the patient's skin through theopenings 29′,29 in adhesive 30. Upon depression of push button switch12, the electronic circuitry on circuit board assembly 18 delivers apredetermined DC current to the electrodes/reservoirs 22,26 and 24,28for a delivery interval of predetermined length, e.g., about 10 minutes.Preferably, the device transmits to the user a visual and/or audibleconfirmation of the onset of the drug delivery, or bolus, interval bymeans of LED 14 becoming lit and/or an audible sound signal from, e.g.,a “beeper”. Analgesic drug, e.g. fentanyl, is then delivered through thepatient's skin, e.g., on the arm, for the predetermined (e.g., 10minute) delivery interval. In practice, a user receives feedback as tothe onset of the drug delivery interval by visual (LED 14 becomes lit)and/or audible signals (a beep from the “beeper”). A preferred device isdescribed in commonly owned, pending patent application entitled“Display for an Electrotransport Device”, Ser. No. 08/410,112, filedMar. 24, 1995, that application being incorporated by reference herein.

Anodic electrode 22 is preferably comprised of silver and cathodicelectrode 24 is preferably comprised of silver chloride. Both reservoirs26 and 28 are preferably comprised of polymer hydrogel materials asdescribed herein. Electrodes 22, 24 and reservoirs 26, 28 are retainedby lower housing 20. When the drug being delivered by electrotransportis cationic, the anodic reservoir 26 is the “donor” reservoir whichcontains the drug and the cathodic reservoir 28 contains a biocompatibleelectrolyte. When the drug being delivered by electrotransport isanionic, the cathodic reservoir 28 is the “donor” reservoir whichcontains the drug and the anodic reservoir 26 contains a biocompatibleelectrolyte.

The push button switch 12, the electronic circuitry on circuit boardassembly 18 and the battery 32 are adhesively “sealed” between upperhousing 16 and lower housing 20. Upper housing 16 is preferably composedof rubber or other elastomeric material. Lower housing 20 is preferablycomposed of a plastic or elastomeric sheet material (e.g., polyethylene)which can be easily molded to form depressions 25,25′ and cut to formopenings 23,23′. The assembled device 10 is preferably water resistant(i.e., splash proof) and is most preferably waterproof. The system has alow profile that easily conforms to the body thereby allowing freedom ofmovement at, and around, the wearing site. The anode/drug reservoir 26and the cathode/salt reservoir 28 are located on the skin-contactingside of device 10 and are sufficiently separated to prevent accidentalelectrical shorting during normal handling and use.

The device 10 adheres to the patient's body surface (e.g., skin) bymeans of a peripheral adhesive 30 which has upper side 34 andbody-contacting side 36. The adhesive side 36 has adhesive propertieswhich assures that the device 10 remains in place on the body duringnormal user activity, and yet permits reasonable removal after thepredetermined (e.g., 24-hour) wear period. Upper adhesive side 34adheres to lower housing 20 and retains the electrodes and drugreservoirs within housing depressions 25,25′ as well as retains lowerhousing 20 attached to upper housing 16.

The push button switch 12 is located on the top side of device 10 and iseasily actuated through clothing. A double press of the push buttonswitch 12 within a short period of time, e.g., three seconds, ispreferably used to activate the device 10 for delivery of drug, therebyminimizing the likelihood of inadvertent actuation of the device 10.

Upon switch activation an audible alarm signals the start of drugdelivery, at which time the circuit supplies a predetermined level of DCcurrent to the electrodes/reservoirs for a predetermined (e.g., 10minute) delivery interval. The LED 14 remains “on” throughout thedelivery interval indicating that the device 10 is in an active drugdelivery mode. The battery preferably has sufficient capacity tocontinuously power the device 10 at the predetermined level of DCcurrent for the entire (e.g., 24 hour) wearing period.

The present invention is particularly useful in the transformation ofhuman skin in the transdermal electrotransport delivery of drugs tohumans. However, the invention also has utility in delivering drugs toother animals and is not limited to humans.

The terms “agent” and “drug” are used interchangeably herein and areintended to have their broadest interpretation as any therapeuticallyactive substance which is delivered to a living organism to produce adesired, usually beneficial, effect. In general, this includestherapeutic agents in all of the major therapeutic areas including, butnot limited to, anti-infectives such as antibiotics and antiviralagents, analgesics and analgesic combinations, anesthetics, anorexics,antiarthritics, antiasthmatic agents, anticonvulsants, anti-depressants,antidiabetic agents, antidiarrheals, antihistamines, anti-inflammatoryagents, antimigraine preparations, antimotion sickness preparations,antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, antispasmodics including gastrointestinaland urinary antispasmodics, anticholinergics, sympathomimetrics,xanthine derivatives, cardiovascular preparations including calciumchannel blockers, beta-blockers, antiarrythmics, antihypertensives,diuretics, vasodilators including general, coronary, peripheral andcerebral vasodilators, central nervous system stimulants, cough and coldpreparations, decongestants, diagnostics, hormones, hypnotics,immunosuppressives, muscle relaxants, parasympatholytics,parasympathomimetrics, proteins, peptides, polypeptides and othermacromolecules, psychostimulants, sedatives and tranquilizers.

The present invention can be used to deliver transdermally byelectrotransport the following drugs: interferons, alfentanyl,amphotericin B, angiopeptin, baclofen, beclomethasone, betamethasone,bisphosphonates, bromocriptine, buserelin, buspirone, calcitonin,ciclopirox, olamine, copper, cromolyn sodium, desmopressin, diclofenacdiflorasone, diltiazem, dobutamine, dopamine agonists, dopamineagonists, doxazosin, droperidol, enalapril, enalaprilat, fentanyl,encainide, G-CSF, GM-CSF, M-CSF, GHRF, GHRH, gonadorelin, goserelin,granisetron, haloperidol, hydrocortisone, indomethacin, insulin,insulinotropin, interleukins, isosorbide dinitrate, ketoprofen,ketorolac, leuprolide, LHRH, lidocaine, lisinopril, LMW heparin,melatonin, methotrexate, metoclopramide, miconazole, midazolam,nafarelin, nicardipine, NMDA antagonists, octreotide, ondansetron,oxybutynin, PGE₁, piroxicam, pramipexole, prazosin, prednisolone,prostaglandins, scopolamine, seglitide, sufentanil, terbutaline,testosterone, tetracaine, tropisetron, vapreotide, vasopressin,verapamil, warfarin, zacopride, zinc, and zotasetron.

This invention is also believed to be useful in the transdermalelectrotransport delivery of peptides, polypeptides and othermacromolecules typically having a molecular weight of at least about 300daltons, and typically a molecular weight in the range of about 300 to40,000 daltons. Specific examples of peptides and proteins in this sizerange include, without limitation, LHRH, LHRH analogs such as buserelin,gonadorelin, nafarelin and leuprolide, GHRH, insulin, heparin,calcitonin, endorphin, TRH, NT-36 (chemical name:N=[[(s)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide),liprecin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate,etc,), follicle luteoids, αANF, growth hormone releasing factor (GHRF),βMSH, TGF-β, somatostatin, atrial natriuretic peptide, bradykinin,somatotropin, platelet-derived growth factor, asparaginase, bleomycinsulfate, chymopapain, cholecystokinin, chorionic gonadotropin,corticotropin (ACTH), epidermal growth factor, erythropoietin,epoprostenol (platelet aggregation inhibitor), follicle stimulatinghormone, glucagon, hirulogs, hyaluronidase, interferons, insulin-likegrowth factors, interleukins, menotropins (urofollitropin (FSH) and LH),oxytocin, streptokinase, tissue plasminogen activator, urokinase,vasopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensin IIantagonists, antidiuretic hormone agonists, antidiuretic hormoneantagonists, bradykinin antagonists, CD4, ceredase, CSF's, enkephalins,FAB fragments, IgE peptide suppressors, IGF-1, neuropeptide Y,neurotrophic factors, opiate peptides, parathyroid hormone and agonists,parathyroid hormone antagonists, prostaglandin antagonists, pentigetide,protein C, protein S, ramoplanin, renin inhibitors, thymosin alpha-1,thrombolytics, TNF, vaccines, vasopressin antagonist analogs, alpha-1anti-trypsin (recombinant).

Generally speaking, it is most preferable to use a water soluble form ofthe drug or agent to be delivered. Drug or agent precursors, i.e.,species which generate the selected species by physical or chemicalprocesses such as ionization, dissociation, dissolution or covalentchemical modification (i.e., prodrugs), are within the definition of“agent” or “drug” herein. “Drug” or “agent” is to be understood toinclude charged and uncharged species as described above.

While the disclosure has focussed upon the electrotransport delivery ofionic species, the present invention is also applicable to theelectrotransport delivery of uncharged species, e.g., by electroosmosis.Thus, the transformation of the skin into the high efficiency transportstate is not limited to electrically assisted transport of ionic speciesbut also to electroosmotic delivery of uncharged (i.e., non-ionized)species.

The following examples illustrate some of the advantages of the presentinvention.

EXAMPLE 1 Current Density and Increased Efficiency

This study evaluated the effect of applied current on electrotransportdrug delivery efficiency. Drug delivery efficiency is expressed in termsof the rate of drug delivery per unit of applied current. The studyinvolved the application of electrotransport devices to eighteen healthymale volunteers for a duration of about one day.

The two electrotransport treatments involved the delivery of fentanyl ata baseline current of 100 μA across a 5 cm² drug-releasing area (i.e.,an applied electrotransport current density of 20 μA/cm²). Six of theeighteen volunteers were administered 4 bolus doses during the firsthour of treatment by applying current levels of 1300 μA (i.e., anapplied electrotransport current density of 260 μA/cm²) for a durationof 2.5 minutes at 15 minute intervals. Following the administration ofthe four boluses in the first hour of treatment, these six volunteersreceived continuous transdermal electrotransport fentanyl administrationat a current density of 20 μA/cm² from hour 2 through 24 hours. Theremaining twelve volunteers received continuous transdermalelectrotransport fentanyl administration at a current density of 20μA/cm² over the entire 24 hour delivery period. After the treatmentperiod, the electrotransport devices were removed. The skin site wasthen washed to remove any residual fentanyl.

Blood samples were taken over the entire 24 hour period commencing withthe application of current from the electrotransport devices. Serumfentanyl concentrations were used to calculate mean fentanyl fluxvalues.

FIG. 5 shows that once a skin site receives a minimum level of current(for a fixed electrode area) for a sufficient duration, a highelectrotransport efficiency state is achieved. FIG. 5 shows the meanserum fentanyl concentration in the blood of the subjects over the 24hour testing period. As is shown in the uppermost curve in FIG. 5, thesix volunteers which received the four 260 μA/cm², 2.5 minute bolusadministrations in the first hour exhibited higher efficiency fentanyltransdermal delivery than the group of twelve subjects shown as threegroups of four in the three lower curves (to emphasize inherentvariability) who received only the 20 μA/cm² constant DC current. Oncethis high-efficiency transport state is achieved, more drug is deliveredthrough the skin per unit of applied current. Further, the effect lastedthe entire 24 hours of the treatment. This is indicated by the verticalseparation between the upper curve and the 3 lower curves.

Specifically, the six volunteers who received the four 260 μA/cm2 dosesin the first hour of treatment exhibited a mean transdermal fentanylrate of 113 μg/h while the twelve volunteers who received only the 20μA/cm2 baseline current exhibited a mean transdermal fentanyl rate of 57μg/h. This indicates that the efficiency was enhanced by about a factorof two as a result of the initial high current density boluses.

Serum fentanyl concentrations were used to calculate the delivery rateusing subject specific pharmacokinetic parameters and conventionalmethods.

EXAMPLE 2 Current Density and Fentanyl Flux

This study was undertaken to evaluate the relationship of currentdensity and drug flux in the transdermal electrotransport delivery offentanyl. Electrotransport devices, delivering constant DC currents,were applied to 8 healthy male volunteers for a duration of 24 hours.The three electrotransport treatment regimens in this study differedonly in the applied electrotransport current (and therefor currentdensity) levels. The electrotransport devices delivered fentanyl throughthe skin from a donor hydrogel having a skin contact surface area of 5cm². The gels were imbibed with an aqueous solution of fentanyl HCl. Thecurrent density levels used in this study were 10, 20, and 40 μA/cm².After a 24 hour treatment period, the electrotransport devices wereremoved. The skin site was then washed to remove any residual fentanyl.All 8 volunteers received each treatment approximately 1 week apart.

For each treatment, blood samples were taken over a 24 hour periodcommencing with the application of current from the electrotransportdevices. Serum fentanyl concentrations over the first 24 hours are shownin FIG. 6. The top curve in FIG. 6 was the 200 μA treatment (i.e., 40μA/cm²), the middle curve the 100 μA treatment (i.e., 20 μA/cm²) and thebottom curve the 50 μA treatment (i.e., 10 μA/cm²). As in Example 1, theserum fentanyl concentrations from each patient were used to calculatemean drug rate and the mean total amount of drug delivered. A drugdelivery efficiency level for each treatment was derived by dividing themean fentanyl rate by the current density applied to the skin.

The average transdermal fentanyl rates were 19, 73 and 173 μg/h at theapplied current densities 10, 20 and 40 μA/cm², respectively. This datashows a non-linear relationship between applied current and drug rate.An almost ten-fold increase in drug rate was observed as the current wasincreased four-fold from 50/JA to 200 μA. This unexpected resultindicates that the efficiency of fentanyl delivery was enhanced by afactor of about 2.5-fold due to the change in current density from 10 to40 μA/cm².

EXAMPLE 3 Pulsing Frequency and Fentanyl Flux

This study assessed the effect of pulsing frequency on theelectrotransport delivery of fentanyl using pulsed current waveforms.The frequencies evaluated in this study were 1, 10, and 625 Hz.

The electrotransport devices were configured to deliver a 200 μA squarewave current pulse, having a 31% duty cycle. The electrotransportdevices delivered fentanyl through the skin from a donor hydrogel havinga skin contact surface area of 2 cm². The gels were imbibed with anaqueous solution of fentanyl HCl. After treatment periods of varyingduration, the electrotransport devices were removed. The skin site wasthen washed to remove any residual fentanyl.

For each treatment, blood samples were taken commencing with theapplication of current from the electrotransport devices. Serum fentanyllevels from each patient were used to calculate mean drug flux.

FIG. 7 shows that the use of a square-wave frequency of 625 Hz resultedin minimal fentanyl flux. This is shown in the lower most nearlyhorizontal line in FIG. 7. The use of the lower pulsing frequencies, 1and 10 Hz, resulted in increased fentanyl flux. This is shown in theupper two curves of FIG. 7. No statistically significant difference infentanyl flux was observed between 1 and 10 Hz. These results suggestthat the use of lower pulsing frequencies results in higherelectrotransport delivery efficiency of fentanyl.

EXAMPLE 4

This study was undertaken to evaluate the relationship between currentdensity and drug flux in the transdermal electrotransport delivery ofgoserelin. The study involved the application of electrotransportdevices, applying constant current, to 12 normal male volunteers for aduration of 8 hours.

The two electrotransport treatment regimens in this study differed onlyin applied current density levels. The electrotransport devicesdelivered goserelin through the skin from polyvinyl alcohol (PVOH)-baseddonor hydrogels having a skin-contact surface area of 4 cm². The gelscontained an aqueous goserelin solution. The current density levels usedin this study were 50 and 100 μA/cm². After an 8 hour treatment period,the electrotransport devices were removed. The skin site was then washedto remove any residual goserelin. All 12 volunteers received eachtreatment seven days apart.

For each treatment, seven blood samples were taken over a 24 hour periodcommencing with the application of current from the electrotransportdevices. Serum goserelin concentrations from each patient were used tocalculate mean drug flux and the mean total amount of drug delivered.

FIG. 8 shows the goserelin blood plasma concentrations for the 8 hourduration of electrotransport administration for the two currentdensities (i.e., 50 and 100 microamperes/square centimeter). The 100μA/cm² curve is the upper curve in FIG. 8 while the lower curve in FIG.8 is the 50 μA/cm² data. From this concentration data, transdermalgoserelin fluxes were calculated. The average transdermal goserelin fluxwas 5.8 microgram per hour at an applied current density of 50microA/cm² while the average transdermal flux of goserelin was 21.6microg/h at an applied current density of 100 microA/cm². Thus, anon-linear relationship between applied current density and drug fluxwas shown by the data. An almost four-fold increase in drug flux isobserved as the current density rises from 50 to 100 μA/cm². This dataalso suggests the existence of a critical current density, l_(c), whichfor transdermal electrotransport delivery of goserelin falls between 50and 100 μA/cm², above which more drug is delivered through the skin perunit of applied current.

The above disclosure will suggest many alternatives, permutations, andvariations of the invention to one skilled in this art without departingfrom the scope of the invention. The above disclosure is intended to beillustrative and not exhaustive. All such, permutations, variations, andalternatives suggested by the above disclosure are to be included withinthe scope of the attached claims.

1. A method of increasing the delivery efficiency of an agent deliveredthrough a body surface by electrotransport, the delivery efficiencybeing equal to the rate of agent delivery through the body surface perunit of applied electric current, comprising delivering the agent byelectrotransport through the body surface by applying current having adensity of about 240 μA/cm² for about 2.5 minutes every 15 minutes for 1hour to transform the body surface to an enhanced, non-transitory agentdelivery efficiency state, and then applying current having a density ofabout 20 μA/cm².
 2. The method of claim 1 wherein the agent is fentanyl.